Comparison of nanoparticle filtration performance of NIOSH-approved and CE-marked particulate filtering facepiece respirators.
The National Institute for Occupational Safety and Health (NIOSH) and European Norms (ENs) employ different test protocols for evaluation of air-purifying particulate respirators commonly referred to as filtering facepiece respirators (FFR). The relative performance of the NIOSH-approved and EN-certified 'Conformité Européen' (CE)-marked FFR is not well studied. NIOSH requires a minimum of 95 and 99.97% efficiencies for N95 and P100 FFR, respectively; meanwhile, the EN requires 94 and 99% efficiencies for FFRs, class P2 (FFP2) and class P3 (FFP3), respectively. To better understand the filtration performance of NIOSH- and CE-marked FFRs, initial penetration levels of N95, P100, FFP2 and FFP3 respirators were measured using a series of polydisperse and monodisperse aerosol test methods and compared. Initial penetration levels of polydisperse NaCl aerosols [mass median diameter (MMD) of 238 nm] were measured using a method similar to the NIOSH respirator certification test method. Monodisperse aerosol penetrations were measured using silver particles for 4-30 nm and NaCl particles for 20-400 nm ranges. Two models for each FFR type were selected and five samples from each model were tested against charge neutralized aerosol particles at 85 l min(-1) flow rate. Penetrations from the 238 nm MMD polydisperse aerosol test were <1% for N95 and FFP2 models and <0.03% for P100 and FFP3 models. Monodisperse aerosol penetration levels showed that the most penetrating particle size (MPPS) was in the 30-60 nm range for all models of FFRs tested in the study. Percentage penetrations at the MPPS were <4.28, <2.22, <0.009 and <0.164 for the N95, FFP2, P100 and FFP3 respirator models, respectively. The MPPS obtained for all four FFR types suggested particle capturing by electrostatic mechanism. Liquid isopropanol treatment of FFRs shifted the MPPS to 200-300 nm and dramatically increased polydisperse as well as monodisperse aerosol penetrations of all four FFR types indicating that all the four FFR types share filtration characteristics of electret filters. Electrostatic charge removal from all four FFR types also increased penetration levels of 400-1000 nm range particles. Particle penetration data obtained in this study showed that the eight models of NIOSH-approved N95 and P100 and CE-marked FFP2 and FFP3 respirators used in this study provided expected levels of laboratory filtration performance against nanoparticles.


REM behavior disorder, hallucinations and cognitive impairment in Parkinson's disease: a two-year follow up.
In Parkinson's disease (PD) the presence of REM parasonnias as REM Behaviour Disorder (RBD) or vivid dreams/nightmares, is recognized as largely associated with hallucinations, even if the risk of the development of hallucinations seem not to depend on how long the REM parasomnias had been occurring. The aim of this study was to establish if RBDs occurring earlier than hallucinations in PD are predictive of cognitive impairment development. Three groups of PD patients: i) group 1, without RBD and without hallucinations; ii) group 2, with RBD but without hallucinations; iii) group 3, with RBD and hallucinations have been prospectively investigated at baseline and after two years throughout a clinical and neuropsychological evaluation. After two years, the group 1 continued to present normal neuropsychological tests and did not present either RBDs or hallucinations. In the group 2, the frontal impairment evidenced at baseline was confirmed; the onset of newly hallucinations was reported in a subgroup of 12 patients, who proved to be older, with a more severe executive impairment at baseline and with a more severe motor symptoms progression than those RBD patients who had not manifested hallucinations. The group 3, characterized at baseline by a more severe cognitive impairment presented, after two years, a cognitive worsening and a higher mortality rate. The longitudinal but at preliminary step investigation identified a PD subgroup of patients, in whom a common background disease profile, including the presence of RBD, could represent a "red flag" in developing further cognitive impairment.


Isolating the role of elevated Phlda2 in asymmetric late fetal growth restriction in mice.
Pleckstrin homology-like domain family A member 2 (PHLDA2) is a maternally expressed imprinted gene whose elevated expression has been linked to fetal growth restriction in a number of human studies. In mice, Phlda2 negatively regulates placental growth and limits the accumulation of placental glycogen. We previously reported that a three-copy transgene spanning the Phlda2 locus drove a fetal growth restriction phenotype late in gestation, suggesting a causative role for PHLDA2 in human growth restriction. However, in this mouse model, Phlda2 was overexpressed by fourfold, alongside overexpression of a second imprinted gene, Slc22a18. Here, we genetically isolate the role of Phlda2 in driving late fetal growth restriction in mice. We furthermore show that this Phlda2-driven growth restriction is asymmetrical, with a relative sparing of the brain, followed by rapid catch-up growth after birth, classic features of placental insufficiency. Strikingly, fetal growth restriction showed strain-specific differences, being apparent on the 129S2/SvHsd (129) genetic background and absent on the C57BL6 (BL6) background. A key difference between these two strains is the placenta. Specifically, BL6 placentae possess a more extensive endocrine compartment and substantially greater stores of placental glycogen. Taken together, these data support a direct role for elevated Phlda2 in limiting fetal growth but also suggest that growth restriction only manifests when there is limited placental reserve. These findings should be taken into account in interpreting the results from human studies.


Altered memory capacities and response to stress in p300/CBP-associated factor (PCAF) histone acetylase knockout mice.
Chromatin remodeling by posttranslational modification of histones plays an important role in brain plasticity, including memory, response to stress and depression. The importance of H3/4 histones acetylation by CREB-binding protein (CBP) or related histone acetyltransferase, including p300, was specifically demonstrated using knockout (KO) mouse models. The physiological role of a related protein that also acts as a transcriptional coactivator with intrinsic histone acetylase activity, the p300/CBP-associated factor (PCAF), is poorly documented. We analyzed the behavioral phenotype of homozygous male and female PCAF KO mice and report a marked impact of PCAF deletion on memory processes and stress response. PCAF KO animals showed short-term memory deficits at 2 months of age, measured using spontaneous alternation, object recognition, or acquisition of a daily changing platform position in the water maze. Acquisition of a fixed platform location was delayed, but preserved, and no passive avoidance deficit was noted. No gender-related difference was observed. These deficits were associated with hippocampal alterations in pyramidal cell layer organization, basal levels of Fos immunoreactivity, and MAP kinase activation. PCAF KO mice also showed an exaggerated response to acute stress, forced swimming, and conditioned fear, associated with increased plasma corticosterone levels. Moreover, learning and memory impairments worsened at 6 and 12 months of age, when animals failed to acquire the fixed platform location in the water maze and showed passive avoidance deficits. These observations demonstrate that PCAF histone acetylase is involved lifelong in the chromatin remodeling necessary for memory formation and response to stress.


Carotid intima-media thickness is inversely associated with olive oil consumption.
Intima-media thickness (IMT) is a valid marker for generalized vascular disease whose main risk factors are associated with food habits and lifestyle. A Mediterranean food pattern may have a protective effect on cardiovascular mortality. To assess the relationship between carotid IMT and olive oil consumption. One hundred and ninety nine patients were randomly extracted from 1055 asymptomatic high cardiovascular risk participants at the AP-UNAV recruitment center of the PREDIMED (PREvención con DIeta MEDiterránea) project. Demographic and clinical variables were collected, and a validated semiquantitative food frequency questionnaire (137 items) was administered at the inclusion interview. A B-mode ultrasound imaging technique was used to measure the mean common carotid IMT. The mean age was 67.3 years and 53.3% were women. Energy-adjusted olive oil consumption quintiles were assessed as the main exposure after adjusting for potential dietary and non-dietary confounders. Using continuous carotid IMT as the outcome in an ANCOVA analysis, the adjusted IMT means throughout quintiles showed an inverse association with a plateau after the second quintile, with statistical differences when the adjusted IMT mean of the merged four upper quintiles were compared with the lowest quintile (p<0.05). The averaged (both sides) mean IMT of the common carotid was dichotomised and values above the median (0.804 mm) were used to identify carotid atherosclerotic damage. We also found an inverse association of olive oil consumption with high IMT, throughout the second to the fifth quintile as compared with the lowest quintile. The adjusted OR was of 0.08 (95% confidence interval, CI, of 0.02-0.37; p=0.001) after merging the four upper quintiles. The inverse association between the olive oil consumption and the carotid IMT could suggest a protective role of olive oil against the development of carotid atherosclerosis in persons at high cardiovascular risk.


The mechanisms of acid-base and ionoregulation in the freshwater rainbow trout during environmental hyperoxia and subsequent normoxia. II. The role of the kidney.
Plasma ionic status and renal excretion of acidic equivalents and electrolytes were continuously monitored in the freshwater rainbow trout (Salmo gairdneri) during 24 h normoxia (PIO2 = 120-150 torr; control); 72 h hyperoxia (PIO2 = 500-600 torr), and 24 h return to normoxia. Plasma [Cl-] progressively declined in approximate equivalence to the rise in [HCO-3] which compensated the respiratory acidosis of hyperoxia, while [Na+] increased only slightly. [Ca2+] and [K+] rose, [phosphate] declined, and [NH+4] was unchanged. During normoxic recovery, the [Na+], [Cl-] and [HCO-3] changes were reversed, [K+] and [Ca2+] showed further elevations, and [NH+4] increased sharply . Renal acid output increased greatly during hyperoxia with elevations in both NH+4 and titratable components, though the latter predominated due to a marked elevation of phosphate excretion. Renal efflux rates of other electrolytes were generally homeostatic for ECF composition, with increased Na+, K+, and Ca2+ effluxes, and decreased Cl- efflux. Clearance calculations indicated that net tubular reabsorption increased for Cl-, fell for Na+ and K+, and changed over to marked net secretion for phosphate, while net ammonia secretion increased. Most trends were reversed upon return to normoxia. The critical role of phosphate in urinary electrolyte balance and acid-base regulation is emphasized. The net renal excretion of acidic equivalents accounted for only 7-10% of the total compensation observed for the whole animal during hyperoxia. The kidney contributed primarily in conserving ECF HCO-3 and secondarily in balancing branchial exchanges.


The bile duct ligated rat: A relevant model to study muscle mass loss in cirrhosis.
Muscle mass loss and hepatic encephalopathy (complex neuropsychiatric disorder) are serious complications of chronic liver disease (cirrhosis) which impact negatively on clinical outcome and quality of life and increase mortality. Liver disease leads to hyperammonemia and ammonia toxicity is believed to play a major role in the pathogenesis of hepatic encephalopathy. However, the effects of ammonia are not brain-specific and therefore may also affect other organs and tissues including muscle. The precise pathophysiological mechanisms underlying muscle wasting in chronic liver disease remains to be elucidated. In the present study, we characterized body composition as well as muscle protein synthesis in cirrhotic rats with hepatic encephalopathy using the 6-week bile duct ligation (BDL) model which recapitulates the main features of cirrhosis. Compared to sham-operated control animals, BDL rats display significant decreased gain in body weight, altered body composition, decreased gastrocnemius muscle mass and circumference as well as altered muscle morphology. Muscle protein synthesis was also significantly reduced in BDL rats compared to control animals. These findings demonstrate that the 6-week BDL experimental rat is a relevant model to study liver disease-induced muscle mass loss.


Associations between active commuting to school and objectively measured physical activity.
To provide more accurate assessment of commuting behavior and potential health effect, it is important to have accurate methods. Therefore, the current study aimed to a) compare questionnaire reported mode of commuting with objectively measured data from accelerometer and cycle computer, b) compare moderate vigorous physical activity (MVPA) among children cycling vs. walking to school, and c) thus calculate possible underestimated MVPA, when using accelerometers to measure commuter cycling. A total of 78 children, average age 11.4 (SD = 0.5), participated in the study. Physical activity was measured with cycle computers and accelerometers for 4 days. Mode of commuting and demographic information was self-reported in a questionnaire. Children who reported to cycle to school spent significantly more time cycling than those who walked to school, 53.6 (SD = ± 33.9) minutes per day vs. 25.5 (SD = ± 24.6) minutes per day (P = .002) (ie, showing that MVPA, measured by accelerometers, underestimated 28.1 minutes per day among children cycling to school vs. those not cycling to school). To provide more accurate assessment of active commuting in children and adolescents future studies should incorporate multiple methodologies such as global position systems (GPS), accelerometers, cycle computers, and self-reported measurements.


Does caregiver well-being predict stroke survivor depressive symptoms? A mediation analysis.
Studies suggest that family caregiver well-being (ie, depressive symptoms and life satisfaction) may affect stroke survivor depressive symptoms. We used mediation analysis to assess whether caregiver well-being might be a factor explaining stroke survivor depressive symptoms, after controlling for demographic factors and stroke survivor impairments and problems. Caregiver/stroke participant dyads (N = 146) completed measures of stroke survivor impairments and problems and depressive symptoms and caregiver depressive symptoms and life satisfaction. Mediation analysis was used to examine whether caregiver well-being mediated the relationship between stroke survivor impairments and problems and stroke survivor depressive symptoms. As expected, more stroke survivor problems and impairments were associated with higher levels of stroke survivor depressive symptoms (P < .0001). After controlling for demographic factors, we found that this relationship was partially mediated by caregiver life satisfaction (29.29%) and caregiver depressive symptoms (32.95%). Although these measures combined to account for 40.50% of the relationship between survivor problems and impairments and depressive symptoms, the direct effect remained significant. Findings indicate that stroke survivor impairments and problems may affect family caregivers and stroke survivors and a high level of caregiver distress may result in poorer outcomes for stroke survivors. Results highlight the likely importance of intervening with both stroke survivors and family caregivers to optimize recovery after stroke.


High-dynamic angle measurement based on laser displacement sensors.
It is currently difficult to achieve good real-time dynamic angle measurements with high accuracy and large ranges. In this paper, a photoelectric measurement method for dynamic angles based on three laser displacement sensors (LDSs) is proposed. Offline, a dynamic angle vision measurement model is established, and the system is calibrated by using a planar target moved by a 2D moving platform. In the course of measurement, three laser beams emitted from three LDSs are projected onto a rotating plane, and three noncollinear points are acquired synchronously; then the rotation angle is calculated in real time. Simulations verify the feasibility of the method theoretically. Experimental results demonstrate that the method achieves measurement accuracies of 0.008° and 0.046° under quasi-static condition of 80°/s and highly dynamic condition of 1000°/s within the measurement range of about ±40°, respectively.


Potential of Fructooligosaccharides and Xylooligosaccharides as Substrates To Counteract the Undesirable Effects of Several Antibiotics on Elder Fecal Microbiota: A First in Vitro Approach.
Fructooligosaccharides (FOS) and xylooligosaccharides (XOS) were employed as substrates for in vitro fermentations to assess their capacity to counteract the effects caused by three antibiotics (ABs) at different doses on the elderly gut microbiota and its metabolic activity. The AB type and dose scarcely affected the total bacterial numbers and the microbiota composition after 24 h. However, in the presence of ABs, the relative percentages of Lactobacillus decreased (from 11.4% to 3.2% in the presence of XOS1), as well as the butyrate production, whereas the population of Bacteroides increased significantly in the presence of XOS1 (from 27.5% to 55.7%). FOS were able to counteract these effects by increasing the butyrate production and the number of Lactobacillus, while maintaining the number of Bacteroides almost constant and decreasing the clostridia. XOS2 (mainly DP = 2-4) also showed ability to increase the percentages of Bifidobacterium and the production of both butyrate and acetate.


BOLD signal within and around white matter lesions distinguishes multiple sclerosis and non-specific white matter disease: a three-dimensional approach.
Multiple sclerosis (MS) diagnostic criteria are based upon clinical presentation and presence of white matter hyperintensities on two-dimensional magnetic resonance imaging (MRI) views. Such criteria, however, are prone to false-positive interpretations due to the presence of similar MRI findings in non-specific white matter disease (NSWMD) states such as migraine and microvascular disease. The coexistence of age-related changes has also been recognized in MS patients, and this comorbidity further poses a diagnostic challenge. In this study, we investigated the physiologic profiles within and around MS and NSWMD lesions and their ability to distinguish the two disease states. MS and NSWMD lesions were identified using three-dimensional (3D) T2-FLAIR images and segmented using geodesic active contouring. A dual-echo functional MRI sequence permitted near-simultaneous measurement of blood-oxygen-level-dependent signal (BOLD) and cerebral blood flow (CBF). BOLD and CBF were calculated within lesions and in 3D concentric layers surrounding each lesion. BOLD slope, an indicator of lesion metabolic capacity, was calculated as the change in BOLD from a lesion through its surrounding perimeters. We observed sequential BOLD signal reductions from the lesion towards the perimeters for MS, while no such decreases were observed for NSWMD lesions. BOLD slope was significantly lower in MS compared to NSWM lesions, suggesting decreased metabolic activity in MS lesions. Furthermore, BOLD signal within and around lesions significantly distinguished MS and NSWMD lesions. These results suggest that this technique shows promise for clinical utility in distinguishing NSWMD or MS disease states and identifying NSWMD lesions occurring in MS patients.


Proximal gut mucosal epithelial homeostasis in aged IL-1 type I receptor knockout mice after starvation.
Previous studies have shown that starvation induces small bowel atrophy, and that atrophy diminishes with aging. In this experiment, we assessed whether starvation-induced atrophy of proximal gut mucosa is associated with the Interleukin-1 receptor (IL-1R) signaling pathway in aged mice. Thirty 26-month-old IL-1R knockout mice and age-matched wild-type C57BL/6 mice were randomly divided into two groups: ad libitum fed and fasted. Mice were euthanized 12 or 48 hours after starvation. The proximal small bowel was harvested for morphologic analysis. Gut epithelial cell proliferation was detected using immunohistochemical staining for proliferating cell nuclear antigen (PCNA), and apoptosis was identified using terminal deoxyuridine nick-end labeling (TUNEL) staining. Aged IL-1R knockout mice were larger than aged-matched wild-type mice (P < 0.05). Proximal gut mucosal height and mucosal cell number were not different between aged IL-1R knockout and wild-type groups. The apoptosis index in gut epithelial cells was higher in fed IL-1R knockout versus wild-type mice (P < 0.05), while there was no significant difference in cell proliferation between both groups. Mucosal atrophy was induced in both aged IL-1R knockout and wild-type groups by starvation (P < 0.05), however, aged IL-1R knockout mice experienced greater loss in proximal gut weight, mucosal length, and corresponding cell number than did wild-type mice at the 12-h time point (P < 0.05). The apoptosis index in gut epithelial cells significantly increased in both groups after starvation (P < 0.05). Starvation decreased cell proliferation in IL-1R knockout mice (P < 0.05), but not in wild-type mice. The response in aged IL-1R knockout mice differs from wild-type mice in that starvation increases atrophy and is associated with decreased cell proliferation rather than increased apoptosis.


A model of meningococcal bacteremia after respiratory superinfection in influenza A virus-infected mice.
We developed a model of sequential influenza A virus (IAV)-Neisseria meningitidis serogroup C (Nm) infection in BALB/c mice. Mice infected intranasally with a sublethal IAV dose (260 pfu) were superinfected intranasally with Nm. Fatal meningococcal pneumonia and bacteremia were observed in IAV-infected mice superinfected with Nm on day 7, but not in those superinfected on day 10. The susceptibility of mice to Nm superinfection was correlated with the peak interferon-gamma production in the lungs and decrease in IAV load. After Nm challenge, both IAV-infected and uninfected control mice produced the inflammatory cytokines interleukin (IL)-1 and IL-6. However, IL-10 was detected in susceptible mice superinfected on day 7 after IAV infection, but not in resistant mice. This model of dual IAV-Nm infection was also used to evaluate the role of bacterial virulence factors in the synthesis of the capsule. A capsule-defective mutant was cleared from the lungs, whereas a mutant inactivated for the crgA gene, negatively regulating expression of the pili and capsule, upon contact with host cells, retained invasiveness. Therefore, this model of meningococcal disease in adult mice reproduces the pathogenesis of human meningococcemia with fatal sepsis, and is useful for analyzing known or new genes identified in genomic studies.


Comprehensive genome and epigenome characterization of CHO cells in response to evolutionary pressures and over time.
The most striking characteristic of CHO cells is their adaptability, which enables efficient production of proteins as well as growth under a variety of culture conditions, but also results in genomic and phenotypic instability. To investigate the relative contribution of genomic and epigenetic modifications towards phenotype evolution, comprehensive genome and epigenome data are presented for six related CHO cell lines, both in response to perturbations (different culture conditions and media as well as selection of a specific phenotype with increased transient productivity) and in steady state (prolonged time in culture under constant conditions). Clear transitions were observed in DNA-methylation patterns upon each perturbation, while few changes occurred over time under constant conditions. Only minor DNA-methylation changes were observed between exponential and stationary growth phase; however, throughout a batch culture the histone modification pattern underwent continuous adaptation. Variation in genome sequence between the six cell lines on the level of SNPs, InDels, and structural variants is high, both upon perturbation and under constant conditions over time. The here presented comprehensive resource may open the door to improved control and manipulation of gene expression during industrial bioprocesses based on epigenetic mechanisms. Biotechnol. Bioeng. 2016;113: 2241-2253. © 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.


Does anterior shoulder balance in adolescent idiopathic scoliosis correlate with posterior shoulder balance clinically and radiographically?
Patients with adolescent idiopathic scoliosis (AIS) often present with a disfiguring shoulder imbalance. Shoulder balance (Sh.B) is of significant importance to the patient's self-perception. Previous studies have correlated Sh.B with respect to only the clinical posterior view correlated with radiographs. It is important, however, to address Sh.B with respect to anterior view of the patients' shoulders as if patients were viewing in a mirror. In this study, we evaluated the anterior Sh.B and correlated it with posterior Sh.B clinically and radiographically in Lenke type 1 and 2 curves. An online scoliosis database was queried to identify 74 AIS patients with Lenke 1 (n = 55, age 15.28 ± 3.35) and 2 (n = 19, age 15.66 ± 3.72) curves with a complete set of PA radiographs and anterior and posterior photos. Radiographic measures for Sh.B included Cobb angles, T1 tilt, first rib angle, and clavicle-rib intersection angle. Clinical measures for Sh.B included inner shoulder angle, outer shoulder angle, and axillary fold angle. Regression analysis with Pearson's correlation and ANOVA for statistical significance was used for analysis. For Lenke 1 curves, there was moderate statistically significant correlation between anterior and posterior clinical Sh.B (R = 0.35-0.41). There was only weak to moderate correlation between radiographic and clinical measures. For Lenke 2 curves, there was a weak to moderate correlation between anterior and posterior clinical Sh.B (R = 0.25-0.45), though not statistically significant. There was no statistically significant correlation between any radiographic measures and posterior Sh.B. There was, however, moderate and significant correlation between radiographic measures and anterior Sh.B. There is no strong correlation between anterior and posterior clinical Sh.B, and surgeons should evaluate both sides in planning deformity correction, especially in Lenke 2 curves. None of the radiographic measures showed strong correlation (R > 0.8) with anterior or posterior clinical Sh.B. A stronger correlation existed between radiographic measures and anterior Sh.B measurements compared with posterior clinical Sh.B measurements in Lenke 2 curves further necessitating anterior evaluation in this group.


Quality of life in women undergoing urinary diversion for bladder cancer: results of a multicenter study among long-term disease-free survivors.
Women undergoing radical cystectomy (RC) and urinary diversion for bladder cancer experience substantial limitations in health-related quality of life (HRQOL). However, the level of discomfort caused by different urinary diversion has been never evaluated in long term survivors. The aim of this multicenter study is to evaluate differences in HRQOL among recurrence-free women undergoing cutaneous ureterostomy (CUS), Bricker's ileal conduit (BK-IC) and Orthotopic neobladder VIP (ONB-VIP) in disease-free females treated with radical cystectomy (RC), with long-term follow up (mean 60.1 months; range 36-122 months). All consecutively treated female patients from two urological institutions who underwent RC and urinary diversion from January 2000 to December 2008, with no evidence of tumor recurrence at a minimum follow up of 36 months, were included. Patients received the European Organisation for Research and Treatment of Cancer (EORTC) generic (QLQ-C30) and bladder cancer-specific instruments (QLQ-BLM30) and the Functional Assessment of Cancer Therapy for Bladder Cancer (FACT-BL). Clinical data and questionnaire results were analyzed in order to evaluate the HRQOL differences among diversion groups. We identified 37 females (median age: 68, range 45-82 years), including 12 status-post CUS, 16 who underwent BK-IC, and 9 who underwent ONB-VIP. Most were healthy (24/37 with no comorbidities, 4/37 Charlson 1-2, 9/37 Charlson 3 or greater - we didn't considered bladder cancer in Charlson evaluation because bladder cancer was the main inclusion criteria). Women undergoing CUS endorsed worse FACT-BL scores compared with BK-IC and ONB-VIP patients, worse HRQOL regarding physical and emotional well-being (p=0.008 and p=0.02, respectively), and a trend toward worse EORTC QLQ-C30 scores for appetite loss and fatigue (p=0.05 for both). In our study long-term disease-free females treated with CUS endorsed worse HRQOL compared with women who underwent BK-IC or ONB-VIP, mostly due to worse physical and emotional perception of their body image.


Complete remission, in BRCA2 mutation carrier with metastatic pancreatic adenocarcinoma, treated with cisplatin based therapy.
Carriers of a germline mutation in the BRCA genes, in particular BRCA2, have an increased risk of developing pancreatic adenocarcinoma when compared with the general population. While the addition of cisplatin to gemcitabine did not produce survival benefit compared to single-agent gemcitabine in prospective trials it is postulated that the addition of DNA cross-linking agent such as cisplatin to standard gemcitabine chemotherapy should be considered in known BRCA mutation carriers. We report a case of pancreatic adenocarcinoma arising in a 60-year-old carrier of a rare BRCA2 (1153insertionT) germline mutation. The patient received gemcitabine without any response and actually progression of the disease had occurred. Therefore cisplatin was added in combination with gemcitabine. A dramatic complete response to therapy was encountered with no evidence of disease in both CT scans and markers (CA19-9). In conclusion, in patients with known BRCA mutation associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin should be considered. Physicians should consider BRCA mutation testing when the diagnosis of pancreatic cancer is established, especially when the patient belongs to an ethnic group where founder mutations exist, and/or there is strong personal or family history of cancer. This may be applied also to other metastatic tumors diagnosed in BRCA1/2 carriers.


Regional differences in neurovascular coupling in rat brain as determined by fMRI and electrophysiology.
Increases in neuronal activity induce local increases in cerebral perfusion. However, our understanding of the processes underlying this neurovascular coupling remains incomplete and, particularly, how these vary across the brain. Recent work supports an important role for astrocytes in neurovascular coupling, in large part via activation of their metabotropic glutamate receptors (mGluR). Here, using a combination of functional magnetic resonance imaging (fMRI) and electrophysiology we demonstrate regional heterogeneity in the mechanisms underlying neurovascular coupling. Direct electrical stimulation of the rat hindpaw sensorimotor cortex induces blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) fMRI responses in several anatomically distinct cortical and subcortical structures. Following intraperitoneal administration of the type 5 mGluR antagonist, MPEP, both BOLD and CBV responses to cortical stimulation were significantly reduced, whilst the local field potential (LFP) responses remained largely constant. Spatially, the degree of reduction in fMRI responses varied between cortical and subcortical regions (primary cortex approximately 18% vs. striatum approximately 66%), and also between primary and secondary cortical areas ( approximately 18% vs. approximately 55%). Similarly, greater decreases in response amplitude were seen in the contralateral secondary cortex ( approximately 91%) and ipsilateral striatum (approximately 70%), compared to the primary cortex (approximately 44%). Following MPEP, a negative component of the BOLD and CBV responses became more apparent, suggesting that different mechanisms mediate vasodilatory and vasoconstrictory responses. Interestingly, under baseline conditions the quantitative relationship between fMRI and LFP responses in cortical and subcortical regions was markedly different. Our data indicate that coupling between neuronal and fMRI responses is neither empirically nor mechanistically consistent across the brain.


Investigation of established genetic risk variants for glioma in prediagnostic samples from a population-based nested case-control study.
Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included. To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research. We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study. Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis. Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology.


Evaluation of Candida albicans formation on feldspathic porcelain subjected to four surface treatment methods.
Candida albicans, known for its adhesion on prosthetic materials and oral tissues, is the most frequently encountered fungal infection in dentistry. The aim of this study was to evaluate the effects of four different surface treatment methods and immersion in artificial saliva on the surface roughness of and candida adhesion on dental porcelains. The four surface treatment methods were namely: natural glaze, overglaze, dual ion exchange, and polishing. Surface roughness of porcelain was evaluated using a surface profilometer and by SEM. Candida adhesion was examined by culturing two Candida strains on porcelain specimens followed by a colorimetric method using XTT/Coenzyme Q0. It became evident that Candida adhesion was found more in the specimens treated with natural glaze and polishing. Further, by the visual inspection of SEM images and comparison of surface roughness, polished and natural-glazed specimens showed rougher surface characteristics than overglazed and dual-ion-exchanged specimens.


The epidemiology of injuries in Atlanta day-care centers.
From June 1987 through May 1988, we collected reports of injuries among 5300 children who attended 71 day-care centers in Atlanta, Ga. One hundred forty-three injuries severe enough for the child to require medical or dental care were reported, including 63 lacerations (44.1%), 23 fractures (16.1%), 5 crush injuries (3.5%), 4 dislocations (2.8%), 2 human bites (1.4%), and 2 concussions (1.4%). The head was the site of 98 (68.5%) injuries. Peak hours for injuries were 11 AM and 4 PM, the peak day was Monday, and the peak season was summer. After adjustment for hours and dates of attendance, the rate was 1.77 injuries per 100,000 child-hours in day care; among preschool-aged children, infants had the lowest rate (0.77) and 2-year-old children had the highest rate (2.26). Almost 47% of injuries occurred on the playground; falls were involved in 70% of such injuries. Because 33% of all injuries resulted from falls on the playground, impact-absorbing playground surfaces may be a possible intervention to reduce injuries.


Shell-core imprinted polyacrylamide crosslinked chitosan for albumin removal from plasma.
Molecularly imprinted polymeric beads were prepared using albumin as the imprinted molecule, acrylamide as the functional monomer, and epichlorhydrin crosslinked chitosan beads as the supporting matrix. The recognition and binding of the imprinted beads was also tested with human plasma for the targeted removal of HSA. Plasma is a rich source of biochemical products that can act as biomarkers of disease or physiological status of a patient. The application of current proteomic technologies in the search for potential diagnostic/prognostic indicators in the plasma of patients is limited by highly abundant albumin that constitute >60% of the total plasma proteins. Removal of abundant proteins will help in the discovery and detection of less abundant proteins that may prove to be informative. The adsorption capacities of the imprinted polymeric beads for pure human serum albumin and plasma albumin were estimated as 92% and 80%, respectively. The easy preparation protocol of derivatised beads and good protein recognition properties make them attractive for biotechnologic approaches.


Hepatic regeneration induces changes in lipoprotein lipase activity in several tissues and its re-expression in the liver.
We examined the expression of lipoprotein lipase (LPL) gene and LPL activity following a two-thirds hepatectomy and during liver regeneration. In most of the tissues studied, LPL activity increased a few hours after partial hepatectomy, but soon returned to normal levels. The greatest increase was found in the adrenal glands, plasma and liver. This increase in LPL activity in the liver could be partially due to an increase in the influx of the enzyme from extrahepatic tissues. There is, however, also a re-expression of LPL mRNA in the liver after partial hepatectomy (during the first hours). It is well known that LPL is expressed in the liver of neonatal animals, but progressively decreases during post-natal development, to reach adult levels around the time of weaning. Our results show by the first time that the remaining liver re-expresses LPL gene during the regeneration process and that the hepatocytes de-differentiate and acquire some of the neonatal characteristics. The increase in LPL mRNA will contribute to the rise in LPL activity after hepatectomy. This presence of LPL could enable the liver to take up fatty acids from the circulating triacylglycerols, which are needed as energetic and plastic substrates during the process of hepatic regeneration.


Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo.
The ability of micro-computed tomography (CT) to noninvasively evaluate allergic pulmonary inflammation in an experimental model was investigated. In addition, two image segmentation methods and the value of respiratory gating were investigated in the context of this model. Brown Norway rats were exposed to one of four doses of house dust mite (HDM) extract (0, 0.15, 15 or 150 microg) delivered intratracheally every 24 h for 10 days. CT scanning was performed at baseline and after several longitudinal HDM exposures. Both thoracic- and lung-segmentation methods yielded similar results when standardisation practices were employed. While tissue histology correlated well with CT images, cell counts from bronchoalveolar lavage depicted greater inflammation than did density measures from CT images. Evidence from representative CT slices and transaxial density distribution indicated that inflammation was primarily associated with major airways and extended into the periphery from these focal points. Respiratory gating demonstrated that images of the inspiratory state provided greater contrast of inflammatory processes. Lastly, decreases in tidal volumes indicated significant mechanical respiratory changes in animals exposed to both 15 and 150 microg. In summary, CT image segmentation can extract pertinent data on in vivo allergic airway/lung inflammation. Furthermore, respiratory gating provides additional contrast and insight into these quantification practices.


Major Cys protease activities are not essential for senescence in individually darkened Arabidopsis leaves.
Papain-like Cys Proteases (PLCPs) and Vacuolar Processing Enzymes (VPEs) are amongst the most highly expressed proteases during leaf senescence in Arabidopsis. Using activity-based protein profiling (ABPP), a method that enables detection of active enzymes within a complex sample using chemical probes, the activities of PLCPs and VPEs were investigated in individually darkened leaves of Arabidopsis, and their role in senescence was tested in null mutants. ABPP and mass spectrometry revealed an increased activity of several PLCPs, particularly RD21A and AALP. By contrast, despite increased VPE transcript levels, active VPE decreased in individually darkened leaves. Eight protease knock-out lines and two protease over expressing lines were subjected to senescence phenotype analysis to determine the importance of individual protease activities to senescence. Unexpectedly, despite the absence of dominating PLCP activities in these plants, the rubisco and chlorophyll decline in individually darkened leaves and the onset of whole plant senescence were unaltered. However, a significant delay in progression of whole plant senescence was observed in aalp-1 and rd21A-1/aalp-1 mutants, visible in the reduced number of senescent leaves. Major Cys protease activities are not essential for dark-induced and developmental senescence and only a knock out line lacking AALP shows a slight but significant delay in plant senescence.


Parental Smoking and Risk of Childhood-onset Type 1 Diabetes.
A few prospective studies suggest an association between maternal smoking during pregnancy and lower risk of type 1 diabetes. However, the role of unmeasured confounding and misclassification remains unclear. We comprehensively evaluated whether maternal smoking in pregnancy predicts lower risk of childhood-onset type 1 diabetes in two Scandinavian pregnancy cohorts (185,076 children; 689 cases) and a Norwegian register-based cohort (434,627 children; 692 cases). We measured cord blood cotinine as an objective marker of nicotine exposure during late pregnancy in 154 cases and 476 controls. We also examined paternal smoking during pregnancy, in addition to environmental tobacco smoke exposure the first 6 months of life, to clarify the role of characteristics of smokers in general. In the pregnancy cohorts, maternal smoking beyond gestational week 12 was inversely associated with type 1 diabetes, pooled adjusted hazard ratio (aHR) 0.66 (95% CI = 0.51, 0.85). Similarly, in the Norwegian register-based cohort, children of mothers who still smoked at the end of pregnancy had lower risk of type 1 diabetes, aHR 0.65 (95% CI = 0.47, 0.89). Cord blood cotinine ≥30 nmol/L was also associated with reduced risk of type 1 diabetes, adjusted odds ratio 0.42 (95% CI = 0.17, 1.0). We observed no associations of paternal smoking during pregnancy, or environmental tobacco smoke exposure, with childhood-onset type 1 diabetes. Maternal sustained smoking during pregnancy is associated with lower risk of type 1 diabetes in children. This sheds new light on the potential intrauterine environmental origins of the disease.


Understanding Social Contagion in Adoption Processes Using Dynamic Social Networks.
There are many studies in the marketing and diffusion literature of the conditions in which social contagion affects adoption processes. Yet most of these studies assume that social interactions do not change over time, even though actors in social networks exhibit different likelihoods of being influenced across the diffusion period. Rooted in physics and epidemiology theories, this study proposes a Susceptible Infectious Susceptible (SIS) model to assess the role of social contagion in adoption processes, which takes changes in social dynamics over time into account. To study the adoption over a span of ten years, the authors used detailed data sets from a community of consumers and determined the importance of social contagion, as well as how the interplay of social and non-social influences from outside the community drives adoption processes. Although social contagion matters for diffusion, it is less relevant in shaping adoption when the study also includes social dynamics among members of the community. This finding is relevant for managers and entrepreneurs who trust in word-of-mouth marketing campaigns whose effect may be overestimated if marketers fail to acknowledge variations in social interactions.


Effects of prenatal alcohol exposure on testosterone and pubertal development.
Animal models have demonstrated fetal alcohol-related disruptions in neuroendocrine function in the hypothalamic-pituitary-gonadal axis and downstream effects on pubertal development and sexual behavior in males and females, but little is known about these effects in humans. This study examined whether prenatal alcohol exposure is associated with alterations in testosterone during adolescence and whether it affects timing of pubertal development. The sample consisted of 265 African American adolescents from the Detroit Longitudinal Cohort Study for whom testosterone and/or pubertal development data were available. Subjects were offspring of women recruited at their first prenatal clinic visit to over represent moderate-to-heavy alcohol use, including a 5% random sample of low-level drinkers/abstainers. Mothers were interviewed at every prenatal visit about their alcohol consumption using a timeline follow-back approach and about their smoking and drug use and sociodemographic factors. At age 14 years, adolescents provided salivary samples, which were analyzed for testosterone (pg/ml), self-reported Tanner stages for pubertal development, and age at menarche (females). Prenatal alcohol exposure was related to elevated testosterone concentrations for males and females but not to changes in Tanner stages or age at menarche, after controlling for confounders. In regression models stratified by alcohol exposure, the expected relation between testosterone and pubic hair development was seen among males with light-to-no prenatal alcohol exposure, but not among those with moderate-to-heavy prenatal alcohol exposure. This interaction between testosterone and prenatal alcohol exposure was confirmed in multivariable models including an alcohol exposure group × testosterone interaction term and potential confounders. This study is the first to show a relation between prenatal alcohol exposure and increased testosterone during adolescence and evidence of decreased testosterone responsiveness in tissues related to pubertal development in humans. Further studies examining androgen receptor expression and other hormonal and cellular factors affecting pubertal development may reveal important mechanisms underlying these teratogenic effects of alcohol exposure.


Chronic obstructive pulmonary disease and comorbidities through the eyes of the patient.
Patient's attitudes and illness beliefs have shown to be of great importance in chronic obstructive pulmonary disease (COPD). As former qualitative research has mainly focused on patients with end-stage COPD, who are recruited within hospital or pulmonary rehabilitation settings, and excluding patients with disabling comorbidities, this study specifically aims to explore the perspectives of patients with COPD and comorbidities in primary care. This study was designed as a qualitative, explorative study using open patient interviews. The study was conducted at three primary care practices, East Flanders, Belgium. A total number of seven patients, diagnosed with COPD and given a minimum score of 2 on the Charlson Comorbidity Index were included. In-depth interviews were recorded and transcribed verbatim. Thematic analysis was deductive using NVivo software. Researchers' triangulation was performed. Participants show high adaptation capabilities and report quite positively about their functional status, with an emphasis on social participation and partnership. Knowledge of the causes and consequences of COPD appears rather limited, and participants predominantly show an external locus of control in relation to the reported factors influencing the disease and strategies for self-management. Patients with COPD with comorbidity integrate their illness and symptoms into their lives. However, a lack of knowledge and education may leave them more anxious and more dependent on health care than necessary. Our results indicate that health care workers should adopt a positive approach toward patient's functioning and empower and inform their patients. We believe that chronic care for patients with COPD should provide personalized rehabilitation taking into account individual patient characteristics and self-management and coping attitudes. We believe that there is a generic core to be identified, which can tackle both COPD and comorbidities. Further research is mandatory to develop these generic programs focusing on patients with complicated needs. Primary care can provide the setting for exploration.


Antimicrobial resistance in Irish isolates of verocytotoxigenic Escherichia coli (E. coli)--VTEC.
This study compared the antimicrobial resistance profiles of Escherichia coli O157:H7 isolates (n=257) recovered from bovine hides, minced beef and human clinical samples in Ireland, to those profiles of a range of Irish non-O157 E. coli (O111 and O26) isolates (n=31) from a variety of clinical and veterinary sources. Four multi-drug resistant (MDR) E. coli O157:H7 food isolates were identified, with resistance to 10 (1 isolate), 6 (1 isolate) and 4 (2 isolates) antimicrobial agents, respectively. Two of these isolates (resistant to 7 and 4 antimicrobial classes) were characterised further by molecular methods and found to contain class 1 integrons along with a beta-lactamase-encoding tem-1 gene. Transfer of antimicrobial resistance (ampicillin, streptomycin and sulphonamides), the tem-1 gene and markers (int1, qacEDelta1, sul1) characteristic of class 1 integrons were evident in one MDR isolate (resistant to 4 antimicrobial classes) when conjugation and transformation experiments were performed. A clinical isolate and a veterinary isolate of the O111 serotype were MDR and resistant to 4 and 3 antimicrobial classes, respectively. These data suggest that the prevalence of antimicrobial resistance among the three VTEC serotypes examined in this study is low. However, these organisms may become a public health risk should they enter the food chain.


Analysis of interactions of DNA polymerase beta and reverse transcriptases of human immunodeficiency and mouse leukemia viruses with dNTP analogs containing a modified sugar residue.
Substrate properties of various morpholinonucleoside triphosphates in the reaction of DNA elongation catalyzed by DNA polymerase beta, reverse transcriptase of human immunodeficiency virus (HIV-1 RT), and reverse transcriptase of Moloney murine leukemia virus (M-MuLV RT) were compared. Morpholinonucleoside triphosphates were utilized by DNA polymerase beta and HIV-1 reverse transcriptase as substrates, which terminated further synthesis of DNA, but were virtually not utilized by M-MuLV reverse transcriptase. The kinetic parameters of morpholinoderivatives of cytosine (MorC) and uridine (MorU) were determined in the reaction of primer elongation catalyzed by DNA polymerase beta and HIV-1 reverse transcriptase. MorC was a more effective substrate of HIV-1 reverse transcriptase and significantly less effective substrate of DNA polymerase beta than MorU. The possible use of morpholinonucleoside triphosphates as selective inhibitors of HIV-1 reverse transcriptase is discussed.


A program for simulated rodent surgical training.
For the inexperienced individual, learning surgical techniques can be taxing. The authors developed a rodent surgery dry lab training program to assist educational and research institutions in providing low-stress training for basic surgical techniques using handmade, cost-effective simulation models. The program not only helps students develop essential skills in basic surgery, but also fulfills the mandate of the 3Rs by allowing students to repeatedly practice and refine their skills on models rather than live animals. This type of training is a valuable tool in bridging the gap between computer training and training with live animals.


SEROLOGICAL STUDIES ON AZOPROTEINS : ANTIGENS CONTAINING AZOCOMPONENTS WITH ALIPHATIC SIDE CHAINS.
A study was made of the specificity of artificial compound-antigens containing aliphatic chains. Striking specificity was exhibited in the reactions of compounds with short chains containing a carboxyl group; for instance succinic acid could be differentiated from malonic or glutaric acid which contain one fewer and one more carbon atom respectively. With the substances containing longer chains, reactions were observed which, although specific to a certain extent, appear to depend mainly on the general physicochemical properties of long aliphatic chains. With a limited number of substances the influence of substituents -halogen, OH, NH(2)-on the serological specificity was investigated. By means of inhibition reactions it was possible to demonstrate the serological specificity of cis-trans isomers such as maleic and fumaric acid.


Natural history of autoimmune thyroiditis.
One hundred and sixty-three asymptomatic people with thyroid antibodies or raised serum thyrotrophin (TSH) concentrations, or both, and 209 age-matched and sex-matched controls without either marker of thyroid disorder were followed up for four years to determine the natural history of autoimmune thyroiditis. Mildly raised TSH concentrations alone and the presence of thyroid antibodies alone did not significantly increase the risk of developing overt hypothyroidism during the four years compared with the controls. Overt hypothyroidism developed at the rate of 5% a year in women who initially had both raised TSH concentrations and thyroid antibodies. Prophylactic treatment with thyroxine may be justified in women found to have both markers of impending thyroid failure. The cost effectiveness of screening the adult population remains to be evaluated.


Complete Genome Sequence of 3-Chlorobenzoate-Degrading Bacterium Cupriavidus necator NH9 and Reclassification of the Strains of the Genera Cupriavidus and Ralstonia Based on Phylogenetic and Whole-Genome Sequence Analyses.
Cupriavidus necator NH9, a 3-chlorobenzoate (3-CB)-degrading bacterium, was isolated from soil in Japan. In this study, the complete genome sequence of NH9 was obtained via PacBio long-read sequencing to better understand the genetic components contributing to the strain's ability to degrade aromatic compounds, including 3-CB. The genome of NH9 comprised two circular chromosomes (4.3 and 3.4 Mb) and two circular plasmids (427 and 77 kb) containing 7,290 coding sequences, 15 rRNA and 68 tRNA genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis of the protein-coding sequences in NH9 revealed a capacity to completely degrade benzoate, 2-, 3-, or 4-hydroxybenzoate, 2,3-, 2,5-, or 3,4-dihydroxybenzoate, benzoylformate, and benzonitrile. To validate the identification of NH9, phylogenetic analyses (16S rRNA sequence-based tree and multilocus sequence analysis) and whole-genome sequence analyses (average nucleotide identity, percentage of conserved proteins, and tetra-nucleotide analyses) were performed, confirming that NH9 is a C. necator strain. Over the course of our investigation, we noticed inconsistencies in the classification of several strains that were supposed to belong to the two closely-related genera Cupriavidus and Ralstonia. As a result of whole-genome sequence analysis of 46 Cupriavidus strains and 104 Ralstonia strains, we propose that the taxonomic classification of 41 of the 150 strains should be changed. Our results provide a clear delineation of the two genera based on genome sequences, thus allowing taxonomic identification of strains belonging to these two genera.


Ab initio simulation of proton spin diffusion.
The many-body nature of the ubiquitous spin diffusion phenomenon makes it difficult to predict accurately from first principles. We show how the use of reduced Liouville spaces makes it possible to reproduce experimental proton spin diffusion measurements directly from crystalline geometry for powdered solids under magic-angle spinning.


Deformation Rate-Adaptive Conducting Polymers and Composites.
Materials are more easily damaged during accidents that involve rapid deformation. Here, a design strategy is described for electronic materials comprised of conducting polymers that defies this orthodox property, making their extensibility and toughness dynamically adaptive to deformation rates. This counterintuitive property is achieved through a morphology of interconnected nanoscopic core-shell micelles, where the chemical interactions are stronger within the shells than the cores. As a result, the interlinked shells retain material integrity under strain, while the rate of dissociation of the cores controls the extent of micelle elongation, which is a process that adapts to deformation rates. A prototype based on polyaniline shows a 7.5-fold increase in ultimate elongation and a 163-fold increase in toughness when deformed at increasing rates from 2.5 to 10 000% min-1 . This concept can be generalized to other conducting polymers and highly conductive composites to create "self-protective" soft electronic materials with enhanced durability under dynamic movement or deformation.


Diagnosis of diaphragmatic trauma with helical CT in a swine model.
The purpose of this study was to determine whether diaphragmatic injury can be accurately diagnosed with helical CT in a swine model. The hypothesis of our study was that thin-section helical CT with sagittal and coronal reformations can reliably detect injury of the diaphragm. The study was performed in a swine model because of the similarity of the swine thorax to the human thorax. Ten swine had a limited abdominal helical CT (enteral contrast; 3-mm collimation; pitch, 1) before and after surgical creation of a 6-cm posterolateral laceration in the left hemidiaphragm. A repeat scan was obtained after 5 cm of gastric fundus was sutured through the laceration. The gastric fundus was used because it is the most commonly herniated viscus in human diaphragmatic injury. No IV contrast was used. Control, laceration, and herniation scans were reconstructed with 1.0-mm overlap and reformated in axial, sagittal, and coronal planes. Three observers scored each reformation as control or injury (defined as laceration or herniation) in a blinded and randomized fashion. Using helical CT, the observers were able to distinguish diaphragmatic injury from controls (p < .0001). The sensitivity and specificity were 92% and 87%, respectively, for sagittal reformations; 85% and 87%, respectively, for coronal reformations; and 73% and 80%, respectively, for axial reformations. Sagittal reformations proved superior to coronal or axial reformations (p = .01). The results were independent of individual observers: We found no significant difference in accuracy among the three observers. Helical CT can accurately detect diaphragmatic injury in a swine model.


Causes behind a human cheese-borne outbreak of gastrointestinal listeriosis.
In a previous paper, we reported an outbreak of gastrointestinal listeriosis due to consumption of fresh cheese made from raw milk and manufactured on a summer farm. The aim of the present study was to investigate why the cheese harbored Listeria monocytogenes. To our knowledge, this is the first documented outbreak of listeriosis caused by raw milk cheese where the human epidemic strain has been cultured from a dairy animal, whose milk has been used for cheese production. The conditions on a summer farm can hardly fulfil the requirements for hygienic and strictly controlled conditions necessary for safe processing of fresh cheese.


Disco funerals: a risk situation for HIV infection among youth in Kisumu, Kenya.
We investigated the so-called 'disco funeral' phenomenon in Kisumu, Kenya, whereby community members including adolescents congregate at the home of the deceased for several days, accompanied by music and dancing. We explored whether disco funerals are a risk situation for HIV/sexually transmitted infection infection among youth. : Cross-sectional qualitative study. We conducted 44 in-depth interviews with male and female adolescents aged 15-20 years in Kisumu municipality in Nyanza Province, Kenya. We also made observations during six disco funerals. Disco funerals were an important place for young people to hang out; they increased the opportunities to meet and engage in (risky) sexual activities. Many adolescents reported having casual sex on these occasions, sometimes with multiple partners, and mostly without condoms. Some girls were forced into sex, and there were several accounts of gang rape. Sex in exchange for money was reported frequently. Drugs and alcohol seemed to facilitate unprotected, multiple-partner, coerced, and transactional sex. In Kisumu, a town with a generalized HIV/AIDS epidemic, the high AIDS mortality leads to frequent disco funerals. Because many adolescents are having unprotected, transactional, or coerced sex at these occasions, disco funerals might contribute to the high HIV prevalence among youth, especially among adolescent girls. HIV interventions urgently need to include outreach actions to youth who hang out at disco funerals and link up with parents and funeral organizers to reduce risk situations.


Mining manufacturing data for discovery of high productivity process characteristics.
Modern manufacturing facilities for bioproducts are highly automated with advanced process monitoring and data archiving systems. The time dynamics of hundreds of process parameters and outcome variables over a large number of production runs are archived in the data warehouse. This vast amount of data is a vital resource to comprehend the complex characteristics of bioprocesses and enhance production robustness. Cell culture process data from 108 'trains' comprising production as well as inoculum bioreactors from Genentech's manufacturing facility were investigated. Each run constitutes over one-hundred on-line and off-line temporal parameters. A kernel-based approach combined with a maximum margin-based support vector regression algorithm was used to integrate all the process parameters and develop predictive models for a key cell culture performance parameter. The model was also used to identify and rank process parameters according to their relevance in predicting process outcome. Evaluation of cell culture stage-specific models indicates that production performance can be reliably predicted days prior to harvest. Strong associations between several temporal parameters at various manufacturing stages and final process outcome were uncovered. This model-based data mining represents an important step forward in establishing a process data-driven knowledge discovery in bioprocesses. Implementation of this methodology on the manufacturing floor can facilitate a real-time decision making process and thereby improve the robustness of large scale bioprocesses.


Randomized trial of drain antisepsis after mastectomy and immediate prosthetic breast reconstruction.
In this 2-site randomized trial, we investigated the effect of antiseptic drain care on bacterial colonization of surgical drains and infection after immediate prosthetic breast reconstruction. With IRB approval, we randomized patients undergoing bilateral mastectomy and reconstruction to drain antisepsis (treatment) for one side, with standard drain care (control) for the other. Antisepsis care included both: chlorhexidine disc dressing at drain exit site(s) and irrigation of drain bulbs twice daily with dilute sodium hypochlorite solution. Cultures were obtained from bulb fluid at 1 week and at drain removal, and from the subcutaneous drain tubing at removal. Positive cultures were defined as ≥1+ growth for fluid and >50 CFU for tubing. Cultures of drain bulb fluid at 1 week (the primary endpoint) were positive in 9.9 % of treatment sides (10 of 101) versus 20.8 % (21 of 101) of control sides (p = 0.02). Drain tubing cultures were positive in 0 treated drains versus 6.2 % (6 of 97) of control drains (p = 0.03). Surgical site infection occurred within 30 days in 0 antisepsis sides versus 3.8 % (4 of 104) of control sides (p = 0.13), and within 1 year in three of 104 (2.9 %) of antisepsis sides versus 6 of 104 (5.8 %) of control sides (p = 0.45). Clinical infection occurred within 1 year in 9.7 % (6 of 62) of colonized sides (tubing or fluid) versus 1.5 % (2 of 136) of noncolonized sides (p = 0.03). Simple and inexpensive local antiseptic interventions with a chlorhexidine disc and hypochlorite solution reduce bacterial colonization of drains, and reduced drain colonization was associated with fewer infections.


Improvement in the measurement of focal length using spot patterns and spherical aberration.
Using an optical setup that includes a square array of 3×3 holes, we used nine meridional rays to measure the effective focal length of a lens. We observed the selected meridional rays as a spot pattern on a diffuse screen. First, we generated a regular square spot pattern (reference pattern) without a lens to test, and then we generated two spot patterns in two different axial positions when the lens being tested refracts the rays. By selecting two sets of four rays of each spot pattern, we were able to measure the difference of the longitudinal (primary) spherical aberration in two positions. With this difference we were able to improve the calculation of the effective focal length. To determine the method's precision, we first simulated the relative error in the effective focal length considering the error in the measurement of the ray heights. Then we determined the experimental relative error by means of the standard deviation of the focal lengths obtained for each spot (in the image of reference and for the images at the two different locations) for both sets of four spots. The experimental results agree very well with the simulation. The error analysis allows us to establish under what conditions it is possible to obtain relative errors of less than 1% in the effective focal length.


Rothia mucilaginosa pneumonia diagnosed by quantitative cultures and intracellular organisms of bronchoalveolar lavage in a lymphoma patient.
Rothia mucilaginosa is a gram-positive coccus of the family Micrococcaceae. R. mucilaginosa is considered a part of the normal flora of the human oropharynx and upper respiratory tract and lower respiratory tract infections attributable to R. mucilaginosa are not frequent. We present a case of pneumonia, in which the R. mucilaginosa infection was diagnosed by quantitative cultures of a bronchoalveolar lavage (BAL) specimen. A 46-yr-old woman with B lymphoblastic lymphoma was admitted to the hospital for scheduled chemotherapy. Her chest computed tomography (CT) scan revealed bilateral multifocal nodular and patchy consolidation in both lungs. Investigation of the BAL specimen revealed that 7% of leukocytes had intracellular gram-positive cocci. The quantitative cultures of the BAL specimen grew mucoid, non-hemolytic, and grayish convex colonies on blood agar at a count of approximately 200,000 colony-forming units/mL. The colonies were identified as R. mucilaginosa. The patient was empirically treated with levofloxacin for 7 days, after which findings on the chest radiograph and CT scan improved. She was discharged with improvement on hospital day 46. To our knowledge, this is the first report of R. mucilaginosa pneumonia diagnosed in Korea. Quantitative culture of BAL specimen and examination of intracellular organisms are crucial for assessing the clinical significance of R. mucilaginosa recovered from the lower respiratory tract.


The shift from a medical to a nursing orientation: A comparison of Swedish nursing students' expectations when entering the nursing degree programme in 2003 and 2013.
The focus of education in nursing has changed over time with a decreased focus on biomedicine and an increased focus on nursing science. It is therefore important to investigate whether these changes are also reflected in the students' conceptions and expectations of the programme over time. The aim of the study was to describe and compare two cohorts of students entering the nursing programme with 10year in between (2003 and 2013), regarding their demographic background, reasons for wanting to become a registered nurse, expectations of the programme and perceptions of the nursing profession. The study was a descriptive cross-sectional cohort study carried out at a university in southern Sweden. In all, 177 nursing students participated in the study, 89 from the 2003 cohort and 88 from the 2013 cohort. Data were collected at the start of the programme using a questionnaire consisting of predefined and open-ended questions. The responses were statistically analysed and compared. The students' reasons for wanting to become a registered nurse remained stable over the 10-year period. The main reason stated by the students in both cohort was humanitarian, i. e wanting to help others. The students' expectations regarding both the programme and the nursing profession had, however, changed significantly from a biomedical to a nursing orientation in the 10-year perspective. The change in the students' preconceptions of the nursing education towards increasing importance of nursing science indicates the beginning of a paradigm shift.


Uterine Fibroids and the Risk of Cardiovascular Disease in the Coronary Artery Risk Development in Young Adult Women's Study.
Uterine fibroids, the most common reproductive tract tumor in women, have been associated with hypertension and atherosclerotic cardiovascular disease (CVD). Prior studies of fibroids and CVD have examined the subset of women with symptomatic fibroids who undergo hysterectomy, itself a risk factor for CVD. We aimed to study the risk of subclinical CVD, as determined by coronary artery calcification (CAC), carotid intima media thickness (CIMT), and left ventricular (LV) mass, in women with ultrasound-diagnosed uterine fibroids. Participants were 972 women from the Coronary Artery Risk Development in Young Adults (CARDIA) study, a cohort recruited in 1985-1986. CARDIA screened black and white women aged 35-49 years by ultrasound for fibroids at 16 years of follow-up (2002-2004). Demographics and CVD risk factors were collected in 2000-2001 at 15 years of follow-up (baseline for this analysis). Women were tested at years 15, 20, and 25 for CAC, at year 20 for CIMT, and at year 25 for echocardiographic LV mass. Multivariable logistic regression was used to estimate the odds of CAC, CIMT, and LV mass. Fifty-two percent of women had fibroids (61.7% in black, 38.3% in white women). Most CVD risk factors were more common in women with fibroids. Adjusted odds of subclinical CVD, such as elevated CIMT and elevated LV mass, were not different for women with fibroids compared with those without (CIMT odds ratio [OR] = 1.03; confidence interval [95% CI] 0.7-1.5 and LV mass OR = 1.14; 95% CI 0.77-1.68), when adjusted for confounders. Although women with fibroids had more CVD risk factors, presence of fibroids was not associated with subclinical CVD.


Evaluation of risk prediction updates from commercial genome-wide scans.
Commercial internet-based companies offer genome-wide scans to predict the risk of common diseases and personalize nutrition and lifestyle recommendations. These risk estimates are updated with every new gene discovery. To assess the benefits of updating risk information in commercial genome-wide scans, we compared type 2 diabetes risk predictions based on TCF7L2 alone, 18 polymorphisms alone, and 18 polymorphisms plus age, sex, and body mass index. Analyses were performed using data from the Rotterdam study, a prospective, population-based study among individuals aged 55 years and older. Data were available from 5297 participants. The actual prevalence of type 2 diabetes in the study population was 20%. Predicted risks were below average for carriers of the TCF7L2 CC genotype (predicted risk 17.6%) and above average for the CT and TT genotypes (20.8% and 28.0%). Adding the other 17 polymorphisms caused 34% of participants to be reclassified (i.e., switched between below and above average): 24% of the CC carriers changed to increased risk, 52% and 6% of the CT and TT carriers changed to decreased risk. Including information on age, sex, and body mass index caused 29% to change categories (27%, 31%, and 19% for CC, CT, and TT carriers, respectively). In total, 39% of participants changed categories once when risk factors were updated, and 11% changed twice, i.e., back to their initial risk category. Updating risk factors may produce contradictory information about an individual's risk status over time, which is undesirable if lifestyle and nutritional recommendations vary accordingly.


Impact of bitter taste receptor phenotype upon clinical presentation in chronic rhinosinusitis.
Genetic variation of the bitter taste receptor T2R38 has been associated with recalcitrant chronic rhinosinusitis (CRS). Specific T2R38 polymorphisms, correlating with bitter taste sensitivity to phenylthiocarbamide (PTC), have been identified as an independent risk factor for surgical intervention in CRS patients without polyps; however, the exact role of PTC tasting ability in clinical practice remains unknown. In this investigation we characterize PTC taste sensitivity in a tertiary care rhinology practice with pertinent clinical measures of disease and quality of life (QOL). Adult CRS patients were prospectively assessed for their ability to taste PTC and categorized as nontasters, tasters, or supertasters. Objective taste was assessed with strips for bitter, sweet, sour, and salty, whereas olfactory testing was measured with Sniffin' Sticks. Correlation was performed between PTC tasting ability and patient demographics, endoscopy scores, validated QOL surveys, and both subjective and objective measures of taste and olfaction. Sixty-seven patients were enrolled. Fifty-two percent were identified as nontasters, 34% as tasters, and 13% as supertasters. Nontasters were more likely to be non-Hispanic (p = 0.018), white (p = 0.027), without nasal polyposis (p = 0.004), and nonasthmatics (p = 0.019). There were no other statistical differences in patients' demographics, QOL measures, and subjective or objective olfactory and taste scores when compared with patients' oral PTC-sensing ability. Oral PTC-sensing ability may serve as a convenient marker of increased disease severity in white CRS patients without polyps and vary among regional populations. PTC tasting ability appears to provide unique phenotypic information not obtained using other subjective or objective measures of smell and taste.


Human leptospirosis caused by a new, antigenically unique Leptospira associated with a Rattus species reservoir in the Peruvian Amazon.
As part of a prospective study of leptospirosis and biodiversity of Leptospira in the Peruvian Amazon, a new Leptospira species was isolated from humans with acute febrile illness. Field trapping identified this leptospire in peridomestic rats (Rattus norvegicus, six isolates; R. rattus, two isolates) obtained in urban, peri-urban, and rural areas of the Iquitos region. Novelty of this species was proven by serological typing, 16S ribosomal RNA gene sequencing, pulsed-field gel electrophoresis, and DNA-DNA hybridization analysis. We have named this species "Leptospira licerasiae" serovar Varillal, and have determined that it is phylogenetically related to, but genetically distinct from, other intermediate Leptospira such as L. fainei and L. inadai. The type strain is serovar Varillal strain VAR 010(T), which has been deposited into internationally accessible culture collections. By microscopic agglutination test, "Leptospira licerasiae" serovar Varillal was antigenically distinct from all known serogroups of Leptospira except for low level cross-reaction with rabbit anti-L. fainei serovar Hurstbridge at a titer of 1:100. LipL32, although not detectable by PCR, was detectable in "Leptospira licerasiae" serovar Varillal by both Southern blot hybridization and Western immunoblot, although on immunoblot, the predicted protein was significantly smaller (27 kDa) than that of L. interrogans and L. kirschneri (32 kDa). Isolation was rare from humans (2/45 Leptospira isolates from 881 febrile patients sampled), but high titers of MAT antibodies against "Leptospira licerasiae" serovar Varillal were common (30%) among patients fulfilling serological criteria for acute leptospirosis in the Iquitos region, and uncommon (7%) elsewhere in Peru. This new leptospiral species reflects Amazonian biodiversity and has evolved to become an important cause of leptospirosis in the Peruvian Amazon.


Pacidamycin biosynthesis: identification and heterologous expression of the first uridyl peptide antibiotic gene cluster.
The pacidamycins are antimicrobial nucleoside antibiotics produced by Streptomyces coeruleorubidus that inhibit translocase I, an essential bacterial enzyme yet to be clinically targeted. The novel pacidamycin scaffold is composed of a pseudopeptide backbone linked by a unique exocyclic enamide to an atypical 3'-deoxyuridine nucleoside. In addition, the peptidyl chain undergoes a double inversion caused by the incorporation of a diamino acid residue and a rare internal ureido moiety. The pacidamycin gene cluster was identified and sequenced, thereby providing the first example of a biosynthetic cluster for a member of the uridyl peptide family of antibiotics. Analysis of the 22 ORFs provided an insight into the biosynthesis of the unique structural features of the pacidamycins. Heterologous expression in Streptomyces lividans resulted in the production of pacidamycin D and the newly identified pacidamycin S, thus confirming the identity of the pacidamycin biosynthetic gene cluster. Identification of this cluster will enable the generation of new uridyl peptide antibiotics through combinatorial biosynthesis. The concise cluster will provide a useful model system through which to gain a fundamental understanding of the way in which nonribosomal peptide synthetases interact.


Conductance-based integrate-and-fire models.
A conductance-based model of Na+ and K+ currents underlying action potential generation is introduced by simplifying the quantitative model of Hodgkin and Huxley (HH). If the time course of rate constants can be approximated by a pulse, HH equations can be solved analytically. Pulse-based (PB) models generate action potentials very similar to the HH model but are computationally faster. Unlike the classical integrate-and-fire (IAF) approach, they take into account the changes of conductances during and after the spike, which have a determinant influence in shaping neuronal responses. Similarities and differences among PB, IAF, and HH models are illustrated for three cases: high-frequency repetitive firing, spike timing following random synaptic inputs, and network behavior in the presence of intrinsic currents.


Conjugated linoleic acid (t-10, c-12) reduces fatty acid synthesis de novo, but not expression of genes for lipid metabolism in bovine adipose tissue ex vivo.
We hypothesized that exogenous fatty acids, and especially or 18:2 trans-10, cis-12 conjugated linoleic acid (CLA), would decrease adipogenic and lipogenic gene expression and de novo fatty acid biosynthesis in intramuscular (i.m.) and subcutaneous (s.c.) adipose tissues. Fresh i.m. and s.c. adipose tissues were collected from the longissimus thoracis muscle of Angus steers at 12, 14, and 16 months of age (n = 4 per time point). Adipose tissue explants were incubated in duplicate for 48 h with 40 μM α-linolenic (ALA), oleic, stearic, trans-vaccenic, or CLA. Adipocyte size, acetate and glucose incorporation into fatty acids in vitro and mRNA levels for C/EBPβ, CPT1β, GPR43, PPARγ, PRKAA1 (AMPKα) and SCD1 were measured following the incubations. PRKAA1 and SCD1gene expression were greater (P < 0.001) in s.c. adipose tissue than in i.m. adipose tissue and acetate incorporation into lipids and C/EBPβ, PPARγ, and SCD1gene expression were greater at 16 months of age than at 12 months of age in i.m. adipose (P < 0.01). C/EBPβ gene expression increased by 16 months of age and PRKAA1 gene expression decreased by 16 months of age in s.c. adipose tissue. All fatty acids increased s.c. adipocyte volumes whereas CLA decreased acetate incorporation into lipids in s.c. adipose tissue (P < 0.05), but none of the fatty acids affected gene expression in i.m. or s.c. adipose tissue (P > 0.10). Thus, CLA depressed de novo fatty acid biosynthesis from acetate but neither CLA nor other fatty acids significantly affected adipogenic or lipogenic gene expression.


Regulation of vascular endothelial growth factor expression by extra domain B segment of fibronectin in endothelial cells.
Diabetic retinopathy entails proliferation of vascular endothelial cells (ECs) and unregulated angiogenesis. We have previously shown that ECs increase the expression of an embryonic variant of fibronectin (FN), called extra domain-B FN (ED-B FN) in response to high glucose. We also showed that ED-B FN regulates EC tube morphogenesis, possibly through vascular endothelial growth factor (VEGF). In the present study, we have attempted to decipher the mechanisms by which ED-B FN may modulate EC phenotype. We hypothesized that ED-B FN regulates VEGF expression in ECs through interaction with selected integrin receptors. To test this hypothesis, we first cultured ECs in high levels of glucose to investigate for any alteration. We then used integrin-specific matrix mimetic peptides, neutralizing antibodies, and RNAi to identify the integrin(s) involved in VEGF expression. Finally, we used an animal model of diabetes to study whether these in vitro mechanisms also take place in the retina. Our results show that exposure of ECs to high levels of glucose increased VEGF expression. ED-B FN mediated this increase since knockdown of ED-B FN completely prevented glucose-induced VEGF expression. We then identified β1 integrin as the essential receptor involved in high glucose-induced VEGF expression. We also showed that diabetes increased β1 integrin and VEGF expression in the retina, which normalized upon ED-B knockdown. These findings showed that high levels of glucose in diabetes increased VEGF expression in ECs through ED-B FN and β1 integrin interaction. These results provide novel mechanistic basis of increased VEGF expression in diabetes.


Density, destinations or both? A comparison of measures of walkability in relation to transportation behaviors, obesity and diabetes in Toronto, Canada.
The design of suburban communities encourages car dependency and discourages walking, characteristics that have been implicated in the rise of obesity. Walkability measures have been developed to capture these features of urban built environments. Our objective was to examine the individual and combined associations of residential density and the presence of walkable destinations, two of the most commonly used and potentially modifiable components of walkability measures, with transportation, overweight, obesity, and diabetes. We examined associations between a previously published walkability measure and transportation behaviors and health outcomes in Toronto, Canada, a city of 2.6 million people in 2011. Data sources included the Canada census, a transportation survey, a national health survey and a validated administrative diabetes database. We depicted interactions between residential density and the availability of walkable destinations graphically and examined them statistically using general linear modeling. Individuals living in more walkable areas were more than twice as likely to walk, bicycle or use public transit and were significantly less likely to drive or own a vehicle compared with those living in less walkable areas. Individuals in less walkable areas were up to one-third more likely to be obese or to have diabetes. Residential density and the availability of walkable destinations were each significantly associated with transportation and health outcomes. The combination of high levels of both measures was associated with the highest levels of walking or bicycling (p<0.0001) and public transit use (p<0.0026) and the lowest levels of automobile trips (p<0.0001), and diabetes prevalence (p<0.0001). We conclude that both residential density and the availability of walkable destinations are good measures of urban walkability and can be recommended for use by policy-makers, planners and public health officials. In our setting, the combination of both factors provided additional explanatory power.


Correlation of the structure and applications of dealloyed nanoporous metals in catalysis and energy conversion/storage.
Nanoporous metals produced by dealloying have shown great promise in many areas such as catalysis/electrocatalysis, energy conversion/storage, sensing/biosensing, actuation, and surface-enhanced Raman scattering. Particularly, nanoscale metal ligaments with high electronic conductivity, tunable size and rich surface chemistry make nanoporous metals very promising as catalysts/electrocatalysts for energy conversion applications such as fuel cells and also as versatile three-dimensional substrates for energy-storage in supercapacitors and lithium ion batteries. In this review, we focus on the recent developments of dealloyed nanoporous metals in both catalysis/electrocatalysis and energy storage. In particular, based on the state-of-the-art electron microscopy characterization, we explain the atomic origin of the high catalytic activity of nanoporous gold. We also highlight the recent advances in rationally designing nanoporous metal-based composites and hierarchical structures for enhanced energy storage. Finally, we conclude with some outlook and perspectives with respect to future research on dealloyed nanoporous metals in catalysis- and energy-related applications.


Sporadic cerebellar ataxia associated with gluten sensitivity.
A total of 104 patients with sporadic cerebellar ataxia were tested for antigliadin and antiendomysium antibodies. Twelve individuals (11.5%) with gluten sensitivity underwent duodenal biopsy and extensive clinical, electrophysiological, neuropsychological, radiological and laboratory investigations including human leucocyte antigen (HLA) typing. Two patients showed typical changes of gluten-sensitive enteropathy with crypt hyperplasia and mucosal flattening. In five patients, the intraepithelial lymphocyte count was elevated. Sporadic ataxia with gluten sensitivity was found to be tightly linked to the HLA DQB1*0201 haplotype (70%). Neurological symptoms were not related to hypovitaminosis or inflammatory CSF changes. The clinical syndrome was dominated by progressive cerebellar ataxia with ataxia of stance and gait (100%), dysarthria (100%) and limb ataxia (97%). Oculomotor abnormalities were gaze-evoked nystagmus (66.7%), spontaneous nystagmus (33.3%), saccade slowing (25%) and upward gaze palsy (16.7%). Extracerebellar features also included deep sensory loss (58.3%), bladder dysfunction (33.3%) and reduced ankle reflexes (33.3%). In accordance with clinical findings, electrophysiological investigations revealed prominent axonal neuropathy with reduced amplitudes (50%) and abnormal evoked potentials (58.3%). On neuropsychological testing, patients presented with moderate verbal memory and executive dysfunction. All patients had evidence of cerebellar atrophy on MRI. We conclude that sporadic ataxia may be associated with positive antibodies against gliadin. Nevertheless, mucosal pathology does not represent an obligatory condition of ataxia with gluten sensitivity. The fact that the disease is strongly associated with the same HLA haplotypes found in coeliac disease not only demonstrates coeliac disease and ataxia with gluten sensitivity to be part of the same disease entity but supports the hypothesis of an immunological pathogenesis of cerebellar degeneration.


Development and Preliminary Evaluation of the Tinnitus Severity Short Form.
Purpose Tinnitus, or the perception of sounds that occur without an external sound source, is a prevalent condition worldwide. For a subset of adults, tinnitus causes significant distress and impairment. Several patient-reported outcome measures have been developed to assess severity of tinnitus distress. However, at present, the field lacks a brief measure that is sensitive to treatment change. The purpose of the current study was to develop and preliminarily validate a brief questionnaire for tinnitus severity from two existing measures of tinnitus-related distress, the Tinnitus Handicap Inventory (THI) and Tinnitus Functional Index (TFI). Method Using data from nine study samples in the United States and United Kingdom, we conducted exploratory and confirmatory factor analyses to identify a short measure with good psychometric properties. We also assessed sensitivity to treatment-related change by examining associations with change in the TFI and THI. Finally, we conducted a confirmatory factor analysis of the final short questionnaire in a new sample of adults seeking treatment for tinnitus-related distress. Results We identified 10 items from the THI and TFI that exhibited limited loadings on secondary factors. The resulting Tinnitus Severity Short Form achieved good to excellent fit, including in a unique sample of individuals seeking online treatment for tinnitus, and appeared sensitive to treatment-related change. Conclusions The Tinnitus Severity Short Form developed in the current study may be a useful tool for the assessment of subjective severity and distress associated with tinnitus, especially when patient burden is a concern. Further research is necessary to fully validate the questionnaire for the assessment of treatment-related change.


Thoracic stop-flow perfusion in the treatment of refractory malignant pleural mesothelioma: a phase I-II evaluation/trial.
Malignant pleural mesothelioma (MPM) is an aggressive treatment-resistant tumor with a median survival from diagnosis of 12 months. Although multimodality protocols that combine aggressive surgery and adjuvant chemotherapy or radiotherapy have shown improved survival in selected cases, the majority of patients with MPM are not suitable for radical surgery due to advanced stage and comorbid medical illness. For these patients combination chemotherapy with Pemetrex and Cisplatin should be considered for first line palliative chemotherapy. The therapeutic options available to patients with MPM resistant or refractory to systemic chemotherapy are very limited. Thoracic "stop-flow" perfusion (TSP) is a semi-invasive loco-regional drug delivery system that, limiting the circulation to the thorax during the anticancer agent's infusion, claims the advantage of reaching high drug concentration at the tumor site while maintaining a low systemic toxicity. The aim of this phase I-II study was to evaluate the toxicity profile and efficacy of two different platinum-based combined regimens--cisplatin plus mitomycin-C (MMC) and cisplatin plus melphalan (L-PAM)--administered using TSP technique in patients with advanced or recurrent MPM who had refractory disease after systemic first line chemotherapy. Patients with histologically proven unresectable stage II-III MPM entered this trial. Between January 1995 and December 2001, 27 patients were enrolled in the study and submitted to TSP using the two different chemotherapy cisplatin based regimens: 12 patients received cisplatin 100 mg/m2 plus MMC 20 mg/m2 (MMC arm) and 15 cisplatin 100 mg/m2 plus L-PAM 50 mg/m2 (L-PAM arm). Objective responses were assessed by CT-scan 30 and 60 days after the end of treatment in all 27 enrolled patients. Two patients (7.4%) achieved a complete response, 2 (7.4%) a partial response and 4 (14.8%) a minor response. The remaining 19 patients (70.3%) showed a stable disease. No patients developed progression of the disease following the first TSP. The overall median time to progression was 8.9 months (range 1-41). The median survival time for all patients from the beginning of regional chemotherapy was 16.6 months, with a 1-year survival rate of 62.9%, a 2-year survival rate of 18.5%, and a 3-year survival rate of 7.4%. Our data show that TSP is a relatively effective second-line treatment in patients with progressive disease after systemic chemotherapy, with a low rate of major complications and treatment-related toxicity.


Air Embolism: Diagnosis, Clinical Management and Outcomes.
Air embolism is a rare but potentially fatal complication of surgical procedures. Rapid recognition and intervention is critical for reducing morbidity and mortality. We retrospectively characterized our experience with air embolism during medical procedures at a tertiary medical center. Electronic medical records were searched for all cases of air embolism over a 25-year period; relevant medical and imaging records were reviewed. Sixty-seven air embolism cases were identified; the mean age was 59 years (range, 3-89 years). Ninety-four percent occurred in-hospital, of which 77.8% were during an operation/invasive procedure. Vascular access-related procedures (33%) were the most commonly associated with air embolism. Clinical signs and symptoms were related to the location the air embolus; 36 cases to the right heart/pulmonary artery, 21 to the cerebrum, and 10 were attributed to patent foramen ovale (PFO). Twenty-one percent of patients underwent hyperbaric oxygen therapy (HBOT), 7.5% aspiration of the air, and 63% had no sequelae. Mortality rate was 21%; 69% died within 48 hours. Thirteen patients had immediate cardiac arrest where mortality rate was 53.8%, compared to 13.5% (p = 0.0035) in those without. Air emboli were mainly iatrogenic, primarily associated with endovascular procedures. High clinical suspicion and early treatment are critical for survival.


Cytotoxic and antitumor activity of a recombinant tumor necrosis factor-B1(Fv) fusion protein on LeY antigen-expressing human cancer cells.
We have constructed a fusion protein composed of tumor necrosis factor alpha (TNF-alpha) fused at its COOH terminus to the scFv region of monoclonal antibody (mAb) B1, an antibody that recognizes LeY antigen present on many human cancer cells. Our rationale for fusing the scFv to the COOH terminus of TNF was to diminish the binding of the fusion protein to TNF receptors because the COOH terminus of TNF is involved in binding, and thus to partially inactivate (detoxify) the molecule. The Fv region should then target and accumulate the fusion protein on cancer cells, which should compensate for the reduced binding affinity of the TNF moiety and lead to selective killing of TNF-sensitive antigen-expressing cancer cells. The fusion protein was expressed in Escherichia coli and found in insoluble inclusion bodies. After refolding and purification by anion exchange, Ni-NTA affinity, and size-exclusion chromatography, we obtained monomeric TNF-B1(Fv). This molecule binds to LeY antigen on cancer cells with the same affinity as B1(scFv) and B1(scFv) immunotoxins but with significantly lower affinity to the TNF receptor compared to the TNF trimer. TNF-B1(Fv) is very toxic to LeY antigen-expressing cancer cells that are sensitive to TNF (e.g., MCF-7 breast or CRL-1739 gastric cancer cells). This cytotoxicity is antibody targeted and TNF mediated because it can be prevented (as shown on MCF-7 cells) by an antibody competing for LeY antigen binding and by an antibody that neutralizes TNF-alpha. TNF-B1(Fv) kills TNF-alpha-sensitive cells that do not express the target antigen only at much higher doses than TNF trimer, and it does not kill LeY-bearing but TNF-alpha-resistant cells. TNF-B1(Fv) can cause significant tumor regression of MCF-7 tumor xenografts in mice at doses that are not toxic to the mice. Thus, the reduced binding of the TNF moiety to TNF receptors, combined with binding of the B1(Fv) portion to LeY antigen, makes TNF-B1(Fv) an agent for selective killing of LeY-expressing TNF-sensitive cancer cells.